This application is a 371 of PCT/JP99/03409, filed Jun. 25, 1999
The present invention relates to amino acid derivatives of the formula (I), process for the preparation thereof and pharmaceutical composition, as active ingredients, them.
More particularly, it relates to amino acid derivatives of the formula (I) 
(wherein all the symbols are the same meanings as hereinafter described), non-toxic salts thereof and the hydrates thereof, processes for the preparation thereof, and N-type calcium channel blocker comprising them as active ingredients.
Calcium ion has been known as an intracellular messenger for signal transduction, and it is suggested that various physiological events are triggered by the elevation of intracellular calcium concentration. Calcium influx from extracellular fluid is one of the mechanisms for the elevation of intracellular calcium concentration. The gate of calcium influx is the voltage-dependent calcium channels. The voltage-dependent calcium channel is opened by the polarization of plasma membrane, and calcium ion influxes from extracellular fluid into the cell selectively through the channel according to the electrochemical gradient. The voltage-dependent calcium channels are classified into N-, L-, P-, Q- and T-type at present. It is known that L- and T-type calcium channels are distributed in the various tissues ubiquitously, and especially, L-type calcium channel is enriched in the smooth muscle cells or the cardiac muscle cells. On the other hand, N- and P-type calcium channels are mainly located in the nervous system and related to the neurotransmitter release. This neurotransmitter is stored in synaptic vesicles of nerve terminals at resting state. When action potential by signal transmission on nerve is conducted in pre-synaptic fiber and reaches to the nerve terminal, the voltage-dependent calcium channels are activated and then, calcium ion influxes into the nerve terminals. By these mechanisms, synaptic vesicles are fused with pre-synaptic membrane, and neurotransmitters in the vesicles are released. The released neurotransmitters are related to signal transmission in synapse due to binding to their receptors in post-synaptic membrane. From the above, an N-type calcium channel blocker is thought to be effective on various diseases induced by an excessive release of neurotransmitter. For example, it may be useful as agent for the prevention and/or treatment of cerebral infarct (J. Cereb. Blood Flow Metab., Vol. 17, 421-429, 1997), transient ischemic attack, encephalomyelopathy after cardiac operation, spinal angiopathy, hypertension with stress (Science., 239, 57-61, 1988), neurosis, epilepsy, asthma or pollakiuria etc. or agent for the treatment of pain (Pain, 60, 83-90, 1995).
The venoms isolated from the genus Conus, xcfx89-conotoxin GVIA, MVIIA, are well known as N-type calcium channel blockers.
But, these xcfx89-conotoxins are peptide compounds, so it is expected that they have various problems (for example, they are not absorbed into the living body easily). Therefore, there is a demand for arrangement of these blockers to non-peptide compounds namely to small-molecule. There are some reports relate to small-molecule as follows:
For example, it is described in the specification of Japanese Patent Kokai Hei 8-217671 that glycine derivatives of the formula (A)
R1ACH(OCOR2A)CH2CONHCH2CO2Hxe2x80x83xe2x80x83(A)
(wherein R1A and R2A are, same or different, C1-19 straight or branched alkyl or C2-19 straight or branched alkenyl) and salts thereof are N-type calcium channel blocker.
It is described in the specification of EP 805147 that the compounds of the formula (B) 
(wherein R1B is alkyl, R2B is hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl, R3B is hydrogen, CN, XB is bond or SO2, R4B, R5B, R6B, R8B, R9B and R10B are each hydrogen or alkyl, AB is CH2 or YBCO (in which YB is bond), R7B is C xcex1-substituent of amino acid or ester thereof, R6B and R7B together form C3-5 alkylene chain optionally substituted by C1-4 alkyl or hydroxy or CH2xe2x80x94ZBxe2x80x94CH2 (in which ZB is CO, S, SO, SO2), R7B and R8B together form C3-5 alkylene chain optionally substituted by C1-4 alkyl or hydroxy, BB is CON(R21B), mB is 0xcx9c2, R11B is hydrogen or alkyl, R12B is hydrogen, alkyl, optionally substituted aryl or optionally substituted heteroaryl, R13B is alkyl, optionally substituted aryl or optionally substituted heteroaryl, R12B and R13B together form C3-8 cycloalkyl), the salts thereof or the ester thereof are calcium channel modulator (necessary part is extracted in the explanation of the group).
Also, it is described in the specification of Japanese Patent Kokai Sho 61-200950 that the compound of the formula (C) 
(wherein RC and R1C each independently, is lower alkyl, aryl-lower alkyl or phenyl optionally substituted by one or more electron-withdrawing or electron-donating group, R2C and R3C each independently, is hydrogen, lower alkyl, aryl-lower alkyl or phenyl optionally substituted with one or more electron-withdrawing or electron-donating group, and nC is 1xcx9c4) and pharmaceutically acceptable salts thereof are anti-convulsant agent.
In addition, the present inventors (applicant(s)) have filed an international application relating to an N-type calcium channel inhibitor (WO99/02146).
Further, as for an application relating to an N-type calcium channel inhibitor, WO 98/54123 is listed.
Besides the above applications, WO 99/25686 (cyclic amine derivatives possessing inhibitory action on chemokine) is listed.
As the result of energetic investigations in order to find compounds possessing inhibitory action on N-type calcium channel, the present inventors have found that the purpose has been accomplished by the compound of the formula (I).
The present invention relates to,
(1) an amino acid derivative of the formula (I) 
wherein,
R1 is,
1) C1-15 alkyl
2) C1-8 alkoxy,
3) phenyl,
4) C3-8 cycloalkyl,
5) heterocyclic ring,
6) C1-4 alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring,
7) C1-4 alkoxy substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring or
8) C2-4 alkenyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring, wherein all the said phenyl, C3-8 cycloalkyl and heterocyclic ring in R1 may be substituted with 1xcx9c3 of substituent(s) selected from the group consisting of the following (i)-(xi):
(i) C1-4 alkyl,
(ii) C1-4 alkoxy,
(iii) phenyl,
(iv) phenoxy,
(v) benzyloxy,
(vi) xe2x80x94SR5 (in which R5 is hydrogen or C1-4 alkyl),
(vii) C2-5 acyl,
(viii) halogen,
(ix) C1-4 alkoxycarbonyl,
(x) nitro and
(xi) xe2x80x94NR6R7 (in which R6 and R7 are independently, hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R6 and R7 taken together with nitrogen atom to which they are attached represents 5xcx9c7-membered saturated heterocyclic ring necessarily containing one nitrogen atom and optionally further containing one nitrogen atom or one oxygen atom),
A is single bond, xe2x80x94COxe2x80x94 or xe2x80x94SO2xe2x80x94,
R2 is hydrogen or C1-4 alkyl which may be substituted with one phenyl,
D is C1-4 alkylene or C2-4 alkenylene,
E is
1) xe2x80x94COOxe2x80x94,
2) xe2x80x94OCOxe2x80x94,
3) xe2x80x94CONR8xe2x80x94 (in which R8 is hydrogen or C1-4 alkyl),
4) xe2x80x94NR9COxe2x80x94 (in which R9 is hydrogen or C1-4 alkyl),
5) xe2x80x94Oxe2x80x94,
6) xe2x80x94Sxe2x80x94,
7) xe2x80x94SOxe2x80x94,
8) xe2x80x94SO2xe2x80x94,
9) xe2x80x94NR10xe2x80x94 (in which R10 is hydrogen or C1-4 alkyl),
10) xe2x80x94COxe2x80x94,
11) xe2x80x94SO2NR11xe2x80x94 (in which R11 is hydrogen or C1-4 alkyl) or
12) xe2x80x94NR12SO2xe2x80x94 (in which R12 is hydrogen or C1-4 alkyl),
R3 is
1) carbocyclic ring,
2) heterocyclic ring or
3) C1-4 alkyl substituted with carbocyclic ring or heterocyclic ring, wherein all the said carbocyclic ring and heterocyclic ring in R3 may be substituted with 1xcx9c3 of substituent(s) selected from the group consisting of the following (i)-(xi):
(i) C1-4 alkyl,
(ii) C1-4 alkoxy,
(iii) phenyl,
(iv) phenoxy,
(v) benzyloxy,
(vi) xe2x80x94SR13 (in which R13 is hydrogen or C1-4 alkyl),
(vii) C2-5 acyl,
(viii) halogen,
(ix) C1-4 alkoxycarbonyl,
(x) nitro and
(xi) xe2x80x94NR14R15 (in which R14 and R15 are independently, hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R14 and R15 taken together with nitrogen atom to which they are attached represents 5xcx9c7-membered saturated heterocyclic ring necessarily containing one nitrogen atom and optionally further containing one nitrogen atom or one oxygen atom),
J is J1 or J2,
J1 is
1) xe2x80x94Oxe2x80x94 or
2) xe2x80x94NR16xe2x80x94 (in which R16 is hydrogen or C1-4 alkyl),
J2 is
1) xe2x80x94NR17xe2x80x94 (in which R17 is C1-4 alkyl substituted with one phenyl, NR18R19 (in which R18 and R19 are independently, hydrogen or C1-4 alkyl), hydroxy, C1-4 alkoxy, xe2x80x94(C1-4 alkylene)-OH, xe2x80x94(C1-4 alkylene)-Oxe2x80x94(C1-4 alkyl) or xe2x80x94(C1-4 alkylene)-Oxe2x80x94(C2-5 acyl)),
2) xe2x80x94NR20xe2x80x94NR21xe2x80x94 (in which R20 and R21 are independently, hydrogen or C1-4 alkyl which may be substituted with one phenyl),
3) xe2x80x94NR22xe2x80x94(C1-4 alkylene)-NR21xe2x80x94 (in which R22 and R23 are independently, hydrogen or C1-4 alkyl which may be substituted with one phenyl),
4) xe2x80x94NR24xe2x80x94(C1-4 alkylene)-Oxe2x80x94 (in which R24 is hydrogen or C1-4 alkyl which may be substituted with one phenyl) or
5) xe2x80x94NR25xe2x80x94(C1-4 alkylene)-Sxe2x80x94 (in which R25 is hydrogen or C1-4 alkyl which may be substituted with one phenyl),
R4 is R4-1, R4-2 or R4-3,
R4-1 is
1) C1-8 alkyl,
2) carbocyclic ring,
3) heterocyclic ring or
4) C1-8 alkyl substituted with 1xcx9c3 of substituent(s) selected from the group consisting of the following (i)-(v);
(i) carbocyclic ring,
(ii) heterocyclic ring,
(iii) COOR26 (in which R26 is hydrogen or C1-4 alkyl substituted with one phenyl (in which the said phenyl may be substituted with C1-4 alkoxy),
(iv) SR27 (in which R27 is hydrogen or C1-4 alkyl) and
(v) OR28 (in which R28 is hydrogen or C1-4 alkyl),
provided that when J is xe2x80x94NR17xe2x80x94, xe2x80x94NR20xe2x80x94NR21xe2x80x94 or xe2x80x94NR22xe2x80x94(C1-4 alkylene)-NR23xe2x80x94, each R4-1 and R17, R4-1 and R21, and R4-1 and R23 taken together with nitrogen atom to which they are attached may represent heterocyclic ring,
wherein all the said carbocyclic ring and heterocyclic ring in R4-1 and the said heterocyclic ring represented by each R4-1 and R17, R4-1 and R21, and R4-1 and R23 taken together with nitrogen atom to which they are attached may be substituted with 1xcx9c3 of the substituent(s) selected from the group consisting of the following (i)-(xi):
(i) C1-4 alkyl,
(ii) C1-4 alkoxy,
(iii) phenyl,
(iv) phenoxy,
(v) benzyloxy,
(vi) xe2x80x94SR29 (in which R29 is hydrogen or C1-4 alkyl),
(vii) C2-5 acyl,
(viii) halogen,
(ix) C1-4 alkoxycarbonyl,
(x) nitro and
(xi) xe2x80x94NR30R31 (in which R30 and R31 are independently, hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R30 and R31 taken together with nitrogen atom to which they are attached represents 5xcx9c7-membered saturated heterocyclic ring necessarily containing one nitrogen atom and optionally further containing one nitrogen atom or one oxygen atom),
R4-2 is
1) carbocyclic ring,
2) heterocyclic ring or
3) C1-8 alkyl substituted with 1xcx9c3 of substituent(s) selected from the group consisting of the following (i)-(v);
(i) carbocyclic ring,
(ii) heterocyclic ring,
(iii) COOR32 (in which R32 is hydrogen or C1-4 alkyl substituted with one phenyl (in which the said phenyl may be substituted with C1-4 alkoxy),
(iv) SR33 (in which R33 is hydrogen or C1-4 alkyl) and
(v) OR34 (in which R34 is hydrogen or C1-4 alkyl),
provided that when J is xe2x80x94NR16xe2x80x94, xe2x80x94NR17xe2x80x94, xe2x80x94NR20xe2x80x94NR21xe2x80x94 or xe2x80x94NR22xe2x80x94(C1-4 alkylene)-NR23xe2x80x94, each R4-2 and R16, R4-2 and R17, R4-2 and R21, and R4-2 and R23 taken together with nitrogen atom to which they are attached may represent heterocyclic ring, wherein at least one ring of all the said carbocyclic ring and heterocyclic ring in R4-2 and the said heterocyclic ring represented by each R4-2 and R16, R4-2 and R17, R4-2 and R21, and R4-2 and R23 taken together with nitrogen atom to which they are attached is substituted with one hydroxy or one xe2x80x94Oxe2x80x94(C1-4 alkylene)-Oxe2x80x94(C1-4 alkyl) and may be substituted with further 1xcx9c2 of substituent(s) selected from the group consisting of the following (i)-(xiii):
(i) C1-4 alkyl,
(ii) C1-4 alkoxy,
(iii) phenyl,
(iv) phenoxy,
(v) benzyloxy,
(vi) xe2x80x94SR35 (in which R35 is hydrogen or C1-4 alkyl),
(vii) C2-5 acyl,
(viii) halogen,
(ix) C1-4 alkoxycarbonyl,
(x) nitro,
(xi) xe2x80x94NR36R37 (in which R36 and R37 are independently, hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R36 and R37 taken together with nitrogen atom to which they are attached represents 5xcx9c7-membered saturated heterocyclic ring necessarily containing one nitrogen atom and optionally further containing one nitrogen atom or one oxygen atom),
(xii) hydroxy and
(xiii) xe2x80x94Oxe2x80x94C1-4 alkylene)-Oxe2x80x94(C1-4 alkyl),
R4-3 is xe2x80x94Lxe2x80x94M,
xe2x80x94Lxe2x80x94 is
1)xe2x80x94(carbocyclic ring which may be substituted with 1xcx9c3 of substituent(s))xe2x80x94,
2)xe2x80x94(heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s))xe2x80x94or
3)xe2x80x94(C1-4 alkylene)-(carbocyclic ring or heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s))xe2x80x94,
provided that when J is xe2x80x94NR16xe2x80x94, xe2x80x94NR17xe2x80x94, xe2x80x94NR20xe2x80x94NR21xe2x80x94 or xe2x80x94NR22xe2x80x94(C1-4 alkylene)-NR23xe2x80x94, each L and R16, L and R17, L and R21, and L and R23 taken together with nitrogen atom to which they are attached may representxe2x80x94(heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s))xe2x80x94,
M is
1) carbocyclic ring or heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s) (with the proviso that when the said carbocyclic ring is phenyl, such a ring is substituted with at least one substituent(s), and that when the said heterocyclic ring is 5xcx9c7-membered saturated heterocyclic ring in which the nitrogen atom in the said heterocyclic ring is bonded to group L shown as 
xe2x80x83and which may contain further one nitrogen atom or one oxygen atom, then such a ring is substituted with at least one substituent(s)),
2) C1-4 alkyl substituted with 1xcx9c2 of substituent(s) selected from the group consisting of the following (i)-(ii);
(i) carbocyclic ring which may be substituted with 1xcx9c3 of substituent(s),
(ii) heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s),
3) xe2x80x94O-(carbocyclic ring or heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s)) (with the proviso that when the said carbocyclic ring is phenyl, such a ring is substituted with at least one substituent(s)),
4) xe2x80x94S-(carbocyclic ring or heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s)),
5) xe2x80x94NR38-(carbocyclic ring or heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s)) (in which R38 is hydrogen or C1-4 alkyl which may be substituted with one phenyl),
6) xe2x80x94Oxe2x80x94CH2-(carbocyclic ring which may be substituted with 1xcx9c3 of substituent(s)) (with the proviso that when the said carbocyclic ring is phenyl, such a ring is substituted with at least one substituent(s)),
7) xe2x80x94Oxe2x80x94(C2-4 alkylene)-(carbocyclic ring which may be substituted with 1xcx9c3 of substituent(s)),
8) xe2x80x94Oxe2x80x94(C1-4 alkylene)-(heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s)),
9) xe2x80x94Sxe2x80x94(C1-4 alkylene)-(carbocyclic ring or heterocyclic ring which may be substituted with 1-3 of substituent(s)),
10) xe2x80x94NR39xe2x80x94(C1-4 alkylene)-(carbocyclic ring or heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s)) (in which R39 is hydrogen, C1-4 alkyl which may be substituted with one phenyl or C2-5 acyl which may be substituted with 1xcx9c3 of halogen) or
11) xe2x80x94CO-(carbocyclic ring or heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s)),
xe2x80x83wherein the substituent(s) of the said carbocyclic ring and heterocyclic ring in L and M and the said heterocyclic ring represented by each L and R16, L and R17, L and R21, and L and R23 taken together with nitrogen atom to which they are attached is selected from the following (i)-(xiv);
(i) C1-4 alkyl,
(ii) C2-4 alkenyl,
(iii) hydroxy,
(iv) C1-4 alkoxy,
(v) xe2x80x94(C1-4 alkylene)-OH,
(vi) xe2x80x94Oxe2x80x94(C1-4 alkylene)-Oxe2x80x94(C1-4 alkyl),
(vii) halogen,
(viii) NR40R41 (in which R40 and R41 are independently, hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R40 and R41 taken together with nitrogen atom to which they are attached represents 5xcx9c7-membered saturated heterocyclic ring necessarily containing one nitrogen atom and optionally further containing one nitrogen atom or one oxygen atom),
(ix) SR42 (in which R42 is hydrogen or C1-4 alkyl),
(x) nitro,
(xi) trifluoromethyl,
(xii) C1-4 alkoxycarbonyl,
(xiii) oxo and
(xiv) C2-5 acyl,
with the proviso that when J is J1, R4 does not represent R4-1] or non-toxic salts thereof, or hydrates thereof,
(2) N-type calcium channel inhibitor comprising, as active ingredient, amino acid derivatives of the formula (I) or non-toxic salts thereof, or hydrates thereof and
(3) process for preparation of amino acid derivatives of the formula (I) or non-toxic salts thereof, or hydrates thereof.
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkenyl, alkynyl and alkylene group includes straight or branched ones. In addition, isomers on double bond, ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generated from asymmetric carbon atom(s) (R-, S-, xcex1-, xcex2-isomer, enantiomer, diastereomer), optically active isomers (D-, L-, d-, I-isomer), polar compounds generated by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, mixtures thereof at voluntary ratios and racemic mixtures are also included in the present invention.
In the formula (I), C1-15 alkyl represented by R1 means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and isomers thereof.
In the formula (I), C1-4 alkoxy represented by R17 means methoxy, ethoxy, propoxy, butoxy and isomers thereof.
In the formula (I), C1-8 alkoxy represented by R1 means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and isomers thereof.
In the formula (I), C3-8 cycloalkyl represented by R1, C3-8 cycloalkyl as a substituent of C1-4 alkyl, C1-4 alkoxy and C2-4 alkenyl in R1 means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In the formula (I), C1-4 alkyl represented by R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R18, R19, R27, R28, R29, R30, R31, R33, R34, R35, R36, R37, R40, R41 and R42 means methyl, ethyl, propyl, butyl and isomers thereof.
In the formula (I), C1-4 alkyl as a substituent of phenyl, C3-8 cycloalkyl and heterocyclic ring in R1, carbocyclic ring and heterocyclic ring in R3, R4, L and M and heterocyclic ring represented by each R4-1 and R17, R4-1 and R21, R4-1 and R23, R4-2 and R16, R4-2 and R17, R4-2 and R21, R4-2 and R23; L and R16, L and R17, L and R21, and L and R23 taken together with nitrogen atom to which they are attached means methyl, ethyl, propyl, butyl and isomers thereof.
In the formula (I), C1-4 alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring represented by R1 means methyl, ethyl, propyl, butyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring and isomers thereof.
In the formula (I), C1-4 alkyl which may be substituted with one phenyl represented by R2, R20, R21, R22, R23, R24, R25, R38 and R39 means methyl, ethyl, propyl, butyl which may be substituted with one phenyl and isomers thereof.
In the formula (I), C1-4 alkyl substituted with one phenyl represented by R17, R26 and R32 means methyl, ethyl, propyl, butyl substituted with one phenyl and isomers thereof.
In the formula (I), C1-4 alkyl substituted with carbocyclic ring or heterocyclic ring represented by R3 means methyl, ethyl, propyl, butyl substituted with carbocyclic ring or heterocyclic ring and isomers thereof.
In the formula (I), C1-4 alkyl in xe2x80x94(C1-4 alkylene)-Oxe2x80x94(C1-4 alkyl) represented by R17 and C1-4 alkyl in xe2x80x94Oxe2x80x94(C1-4 alkylene)-Oxe2x80x94(C1-4 alkyl) as a substituent of carbocyclic ring or heterocyclic ring in R4-2, L and M and heterocyclic ring represented by each R4-2 and R16, R4-2 and R17, R4-2 and R21, R4-2 and R23, L and R16, L and R17, L and R21, and L and R23 taken together with nitrogen atom to which they are attached means methyl, ethyl, propyl, butyl and isomers thereof.
In the formula (I), C1-4 alkyl substituted with 1xcx9c2 of substituent(s) selected from the group consisting of group (i)-(ii) represented by M means methyl, ethyl, propyl, butyl substituted with 1xcx9c2 of substituent(s) selected from the group consisting of group (i)-(ii) and isomers thereof.
In the formula (I), C1-8 alkyl represented by R4-1 means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.
In the formula (I), C1-8 alkyl substituted with 1xcx9c3 of substituent(s) selected from the group consisting of group (i)-(v) represented by R4-1 and R4-2 means methyl, ethyl, propyl, butyl, propyl, pentyl, hexyl, heptyl, octyl substituted with 1xcx9c3 of substituent(s) selected from the group consisting of group (i)-(v) and isomers thereof.
In the formula (I), C1-4 alkoxy substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring represented by R1 means methoxy, ethoxy, propoxy, butoxy substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring and isomers thereof.
In the formula (I), C1-4 alkoxy as a substituent of phenyl, C3-8 cycloalkyl and heterocyclic ring in R1, C1-4 alkoxy as a substituent of carbocyclic ring and heterocyclic ring in R3, R4, L and M, and C1-4 alkoxy as a substituent of heterocyclic ring represented by each R4-1 and R17, R4-1 and R21, R4-1 and R23, R4-2 and R16, R4-2 and R17, R4-2 and R21, R4-2 and R23, L and R16, L and R17, L and R21, and L and R23 taken together with nitrogen atom to which they are attached mean methoxy, ethoxy, propoxy, butoxy and isomers thereof.
In the formula (I), C1-4 alkoxy as a substituent of phenyl in C1-4 alkyl substituted with one phenyl in R26 and R32 means methoxy, ethoxy, propoxy, butoxy and isomers thereof.
In the formula (I), C2-4 alkenyl substituted with phenyl, cycloalkyl or heterocyclic ring represented by R1 means ethenyl, propenyl, butenyl substituted with phenyl, cycloalkyl or heterocyclic ring and isomers thereof.
In the formula (I), C2-4 alkenyl as a substituent of carbocyclic ring, heterocyclic ring in L and M, and C2-4 alkenyl as a substituent of heterocyclic ring represented by each L and R16, L and R17, L and R21, and L and R23 taken together with nitrogen atom to which they are attached means ethenyl, propenyl, butenyl and isomers thereof.
In the formula (I), C2-5 acyl in xe2x80x94(C1-4 alkylene)-Oxe2x80x94(C2-5 acyl) represented by R17 means acetyl, propionyl, butyryl, valeryl and isomers thereof.
In the formula (I), C2-5 acyl may be substituted with 1xcx9c3 of halogen represented by R39 means acetyl, propionyl, butyryl, valeryl may be substituted with 1xcx9c3 of halogen and isomers thereof.
In the formula (I), C2-5 acyl as a substituent of phenyl, C3-8 cycloalkyl and heterocyclic ring in R1, C2-5 acyl as a substituent of carbocyclic ring, heterocyclic ring in R3, R4, L and M, and C2-5 acyl as a substituent of heterocyclic ring represented by each R4-1 and R17, R4-1 and R21, R4-1 and R23, R4-2 and R16, R4-2 and R17, R4-2 and R21, R4-2 and R23, L and R16, L and R17, L and R21, and L and R23 taken together with nitrogen atom to which they are attached means acetyl, propionyl, butyryl, valeryl and isomers thereof.
In the formula (I), halogen as a substituent of C2-5 acyl represented by R39, halogen as a substituent of phenyl, C3-8 cycloalkyl and heterocyclic ring in R1, halogen as a substituent of carbocyclic ring and heterocyclic ring in R3, R4, L and M, halogen as a substituent of heterocyclic ring represented by each R4-1 and R17, R4-1 and R21, R4-1 and R23, R4-2 and R16, R4-2 and R17, R4-2 and R23, L and R16, L and R17, L and R21, and L and R23 taken together with nitrogen atom to which they are attached mean fluoride, chloride, bromide and iodide.
In the formula (I), C1-4 alkoxycarbonyl represented by R6, R7, R14, R15, R30, R31, R36, R37, R40, and R41 means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and isomers thereof.
In the formula (I), C1-4 alkoxycarbonyl as a substituent of phenyl, C3-8 cycloalkyl and heterocyclic ring in R1, C1-4 alkoxycarbonyl as a substituent of carbocyclic ring and heterocyclic ring in R3, R4, L and M, and C1-4 alkoxycarbonyl as a substituent of heterocyclic ring represented by each R4-1 and R17, R4-1 and R21, R4-1 and R23, R4-2 and R16, R4-2 and R17, R4-2 and R21, R4-2 and R23, L and R16, L and R17, L and R21, and L and R23 taken together with nitrogen atom to which they are attached means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and isomers thereof.
In the formula (I), C1-4 alkylene represented by D means methylene, ethylene, propylene, butylene and isomers thereof.
In the formula (I), C1-4 alkylene in xe2x80x94NR22xe2x80x94(C1-4 alkylene)-NR23xe2x80x94, xe2x80x94NR24xe2x80x94 (C1-4 alkylene)-Oxe2x80x94 and xe2x80x94NR25xe2x80x94((C1-4 alkylene)-Sxe2x80x94 represented by J2, C1-4 alkylene in xe2x80x94(C1-4 alkylene)-OH, xe2x80x94(C1-4 alkylene)-Oxe2x80x94(C1-4 alkyl) and xe2x80x94(C1-4 alkylene)-Oxe2x80x94(C2-5 acyl) represented by R17, C1-4 alkylene in xe2x80x94(C1-4 alkylene)-(carbocyclic ring or heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s))xe2x80x94represented by L, or C1-4 alkylene in xe2x80x94Oxe2x80x94(C1-4 alkylene)-(heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s)), xe2x80x94Sxe2x80x94(C1-4 alkylene)-(carbocyclic ring or heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s)) and xe2x80x94NR39xe2x80x94(C1-4 alkylene)-(carbocyclic ring or heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s)) represented by M means methylene, ethylene, propylene, butylene and isomers thereof.
In the formula (I), C2-4 alkylene in xe2x80x94Oxe2x80x94(C2-4 alkylene)-(carbocyclic ring which may be substituted with 1xcx9c3 of substituent(s)) represented by M means ethylene, propylene, butylene and isomers thereof.
In the formula (I), C1-4 alkylene in xe2x80x94Oxe2x80x94(C1-4 alkylene)-Oxe2x80x94(C1-4 alkyl) as a substituent of carbocyclic ring or heterocyclic ring in R4, L and M and heterocyclic ring represented by each R4-2 and R16, R4-2 and R17, R4-2 and R21, R4-2 and R23, L and R16, L and R17, L and R21, and L and R23 taken together with nitrogen atom to which they are attached mean methylene, ethylene, propylene, butylene and isomers thereof.
In the formula (I), C1-4 alkylene in xe2x80x94(C1-4 alkylene)-OH as a substituent of carbocyclic ring or heterocyclic ring in L and M and heterocyclic ring represented by each L and R16, L and R17, L and R21, and L and R23 taken together with nitrogen atom to which they are attached means methylene, ethylene, propylene, butylene and isomers thereof.
In the formula (I), C2-4 alkenylene represented by D means ethenylene, propenylene, butenylene and isomers thereof.
In the formula (I), 5xcx9c7-membered saturated heterocyclic ring necessarily containing one nitrogen atom and optionally further containing one nitrogen atom or one oxygen atom represented by each R6 and R7, R14 and R15, R30 and R31, R36 and R37, and R40 and R41 taken together with nitrogen atom to which they are attached means, for example, pyrrolidine, piperidine, piperazine, morpholine, perhydroazepine.
In the formula (I), carbocyclic ring in R3, R4, L and M means C3-10 mono-, bi-carbocyclic ring and fused carbocyclic ring. The said C3-10 mono-, bi-carbocyclic ring and fused carbocyclic ring means, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopenten, cyclohexen, cyclopentadien, cyclohexadien, benzene, pentalene, indene, naphathalene, azulene, dihydronaphathalene, tetrahydronaphathalene, perhydronaphathalene, indane (dihydroindene), perhydroindene, bicyclopentane, bicyclohexane, bicycloheptane (bicyclo[2.2.1]heptane), bicyclohepten (bicyclo[2.2.1]hept-2-en), bicyclooctane, bicyclononane, bicyclodecane, adamantane etc.
In the formula (I), heterocyclic ring in R1, R3, R4, L and M means 5xcx9c15-membered mono- or bi-heterocyclic ring containing 1xcx9c2 nitrogen atom(s), 1xcx9c2 oxygen atom(s) and/or one sulfur atom which is unsaturated or saturated partially or fully (abbreviated as heterocyclic ring (A)). The said 5xcx9c15-membered mono- or bi-heterocyclic ring containing 1xcx9c2 nitrogen atom(s), 1xcx9c2 oxygen atom(s) and/or one sulfur atom which is unsaturated or saturated partially or fully means, for example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, hexahydroazepine, dihydrofran, tetrahydrofran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain (dihydrothiopyran), tetrahydrothiain (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisooxazole, tetrahydroisooxazole, dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetraisothiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthylidine, tetrahydronaphthylidine, perhydronaphthylidine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzooxazole, perhydrobenzooxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole, dihydrobenzooxazine, dioxaindane, benzodioxane, quinuclidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridazine, azepine, diazepine, fran, pyran, oxepine, oxazepine, thiophene, thiain (thiopyran), thiepine, oxazole, isooxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofran, isobenzofran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthylidine, quinoxaline, quinazoline, cinnoline, benzooxazole, benzothiazole, benzoimidazole, oxatetrahydrofran etc.
In the formula (I), heterocyclic ring represented by each R4-1 and R17, R4-1 and R21, R4-1 and R23, R4-2 and R16, R4-2 and R17, R4-2 and R23, L and R16, L and R17, L and R21, and L and R23 taken together with nitrogen atom to which they are attached means 5xcx9c15-membered mono- or bi-heterocyclic ring containing one nitrogen atom as an essential and optionally further containing one nitrogen atom, one oxygen atom and/or one sulfur atom which is unsaturated or saturated partially or fully. The said 5xcx9c15-membered mono- or bi-heterocyclic ring containing one nitrogen atom as an essential and optionally further containing one nitrogen atom, 1xcx9c2 oxygen atom and/or one sulfur atom which is unsaturated or saturated partially or fully means, for example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrim idine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, hexahydroazepine, tetrahydrooxazole, tetrahydroisooxazole, tetrahydrothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthylidine, tetrahydronaphthylidine, perhydronaphthylidine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzooxazole, perhydrobenzooxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole, pyrrole, imidazole, pyrazole, indole, isoindole, indazole, benzoimidazole etc.
R1 is preferably C1-8 alkoxy, phenyl, C3-8 cycloalkyl, heterocyclic ring or C1-4 alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring, and more preferably heterocyclic ring (provided that all the said phenyl, cycloalkyl and heterocyclic ring may be substituted). The said heterocyclic ring (A) is listed as for such a heterocyclic ring. More preferablly, such a ring is 5xcx9c15-membered mono- or bi-heterocyclic ring containing 1xcx9c2 nitrogen atom(s), 1xcx9c2 oxygen atom(s) and/or one sulfur atom which is unsaturated or saturated partially or fully (for example, dihydrooxazole, tetrahydrooxazole, dihydroisooxazole, tetrahydroisooxazole, dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetraisothiazole, morpholine, thiomorpholine, dihydrobenzooxazole, perhydrobenzooxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzooxazine, oxazepine, oxazole, isooxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, benzooxazole, benzothiazole etc.), and more preferably, 5xcx9c7-membered mono-heterocyclic ring containing one nitrogen atom and one oxygen atom or one sulfur atom which is unsaturated or saturated partially or fully (for example, dihydrooxazole, tetrahydrooxazole, dihydroisooxazole, tetrahydroisooxazole, dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetraisothiazole, morpholine, thiomorpholine, oxazepine, oxazole, isooxazole, thiazole, isothiazole, oxazine, oxazepine, thiazine, thiazepine etc.) and most preferably, tetrahydrothiazole (thiazolidine).
A is preferably single bond or xe2x80x94COxe2x80x94, and more preferably xe2x80x94COxe2x80x94.
D is preferably each group, more preferably C1-4 alkylene, and most preferably methylene.
R2 is preferably each group, more preferably hydrogen or methyl substituted with one phenyl, and most preferably hydrogen.
E is preferably xe2x80x94COOxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, more preferably xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and most preferably xe2x80x94Sxe2x80x94.
R3 is preferably carbocyclic ring or C1-4 alkyl substituted with carbocyclic ring (all the said carbocyclic ring may be substituted), more preferably C3-10 cycloalkyl such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane or C1-4 alkyl substituted with C3-10 cycloalkyl (all the said cycloalkyl may be substituted), much more preferably cyclopentyl or cyclohexyl or methyl substituted with cyclopentyl or cyclohexyl, and most preferably methyl substituted with cyclohexyl.
J is preferably xe2x80x94NR16xe2x80x94 (in which R16 is the same meaning as defined hereinbefore) or xe2x80x94NR22xe2x80x94(C1-4 alkylene)-NR23xe2x80x94 (in which R22 and R23 are the same meanings as defined hereinbefore), and more preferably xe2x80x94NR16xe2x80x94.
R4 is preferably (xe2x80x94Lxe2x80x94M) represented by R4-3.
In the above symbol, L is preferably each group, and more preferably heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s). The said heterocyclic ring (A) is listed as such a heterocyclic ring. More preferably, such a ring is 5xcx9c15-membered mono- or bi-heterocyclic ring containing 1xcx9c2 nitrogen atom(s) which is unsaturated or saturated partially or fully (for example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, hexahydroazepine, indoline, isoindoline, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthylidine, tetrahydronaphthylidine, perhydronaphthylidine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoimidazole, perhydrobenzoimidazole, quinuclidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridazine, azepine, diazepine, indole, isoindole, indazole, quinoline, isoquinoline, phthalazine, naphthylidine, quinoxaline, quinazoline, cinnoline, benzoimidazole etc.), and more preferably, 5xcx9c7-membered mono-heterocyclic ring containing 1xcx9c2 nitrogen atom(s) which is unsaturated or saturated partially or fully (for example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, hexahydroazepine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridazine, azepine, diazepine etc.) and most preferably piperidine.
M is preferably each group, more preferably C1-4 alkyl substituted with 1xcx9c2 of substituent(s) selected from the group consisting of carbocyclic ring or heterocyclic ring which may be substituted with 1xcx9c3 of substituent(s), and more preferably C1-4 alkyl substituted with 1xcx9c2 of substituent(s) selected from the group consisting of phenyl and C3-10 cycloalkyl which may be substituted with 1xcx9c3 of substituent(s), and most preferably methyl substituted with one phenyl.
Each ring in R1 is preferably ring which is unsubstituted or substituted, more preferably ring which is unsubstituted or substituted with C1-4 alkyl, halogen, C1-4 alkoxycarbonyl, and most preferably ring substituted with C1-4 alkoxycarbonyl.
The substituent of ring in R4 or substituent of heterocyclic ring represented by J and R4 is preferably each group (in case of unsubstituted ring, such an unsubstituted ring is also preferable).
In R4, preferably at least one of carbocyclic ring and heterocyclic ring in R4-2 and heterocyclic ring represented by each R4-2 and R16, R4-2 and R17, R4-2 and R21, and R4-2 and R23 taken together with nitrogen atom to which they are attached is substituted with one hydroxy and heterocyclic ring which may be substituted with 1xcx9c2 of substituent(s) selected from the group consisting of the following (i)-(xii):
(i) C1-4 alkyl,
(ii) C1-4 alkoxy,
(iii) phenyl,
(iv) phenoxy,
(v) benzyloxy,
(vi) xe2x80x94SR35 (in which R35 is hydrogen or C1-4 alkyl),
(vii) C2-5 acyl,
(viii) halogen,
(ix) C1-4 alkoxycarbonyl,
(x) nitro,
(xi) xe2x80x94NR36R37 (in which R36 and R37 are independently, hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R36 and R37 taken together with nitrogen atom to which they are attached represents 5xcx9c7-membered saturated heterocyclic ring necessarily containing one nitrogen atom and optionally further containing one nitrogen atom or one oxygen atom) and
(xii) hydroxy
is preferable.
In addition, in R4, the substituent of carbocyclic ring and heterocyclic ring in L and M, and the substituent of heterocyclic ring represented by each L and R16, L and R17, L and R21, and L and R23 taken together with nitrogen atom to which they are attached is preferably group selected from the following (i)-(v) and (vii)-(xiv):
(i) C1-4 alkyl,
(ii) C2-4 alkenyl,
(iii) hydroxy,
(iv) C1-4 alkoxy,
(v) xe2x80x94(C1-4 alkylene)-OH,
(vii) halogen,
(viii) NR40R41 (in which R40 and R41 are independently, hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R40 and R41 taken together with nitrogen atom to which they are attached, represents 5xcx9c7-membered saturated heterocyclic ring necessarily containing one nitrogen atom and optionally further containing one nitrogen atom or one oxygen atom),
(ix) SR42 (in which R42 is hydrogen or C1-4 alkyl),
(x) nitro,
(xi) trifluoromethyl,
(xii) C1-4 alkoxycarbonyl,
(xiii) oxo and
(xiv) C2-5 acyl.
[Salts]
All the non-toxic salts are also included in the present invention. For example, the compounds of the formula (I) of the present invention may be converted into the corresponding salts by known methods. Non-toxic and water-soluble salts are preferable. Suitable salts, for example, are follows: salts of alkaline metals (potassium, sodium etc.), salts of alkaline earth metals (calcium, magnesium etc.), ammonium salts, salts of pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, dicyclohexylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine, N-methyl-D-glucamine etc.).
The compounds of the formula (I) of the present invention may be converted into the corresponding acid additional salts by methods known per se. Non-toxic and water-soluble acid addition salts are preferable. Suitable acid addition salts, for example, are salts of inorganic acids, e.g., hydrochloride, hydrobromide, sulphate, phosphate, nitrate etc., or salts of organic acids, e.g., acetate, trifluoroacetate, lactate, tartarate, oxalate, fumarate, maleate, citrate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, toluenesulphonate, isethioate, glucuronate, gluconate etc.
The compounds of the formula (I) of the present invention or salts thereof may be converted into hydrate thereof by methods known per se.
In the compounds of the formula (I), the compounds of the formula (Ia) 
(wherein all the symbols are the same meanings as defined hereinbefore), the compounds of the formula (Ib) 
(wherein all the symbols are the same meanings as defined hereinbefore), the compounds of the formula (Ic) 
(wherein all the symbols are the same meanings as defined hereinbefore), the compounds of the formula (Id) 
(wherein all the symbols are the same meanings as defined hereinbefore), the compounds of the formula (Ie) 
(wherein all the symbols are the same meanings as defined hereinbefore), the compounds of the formula (If) 
(wherein all the symbols are the same meanings as defined hereinbefore), the compounds of the formula (Ig) 
(wherein all the symbols are the same meanings as defined hereinbefore), and the compounds of the formula (Ih) 
(wherein all the symbols are the same meanings as defined hereinbefore), non-toxic salts thereof or hydrates thereof are prefereable. The compounds of the formula (Ia) or (Ib) (wherein all the symbols are the same meanings as defined hereinbefore), non-toxic salts thereof or hydrates thereof are more preferable.
The concrete compounds are ones shown in the following Tables 1-40, non-toxic salts thereof and the hydrates thereof and ones described in Examples. Also, the following concrete compounds include the isomers generated by asymmetric carbon atom(s), i.e., R, S and RS form. In the following each Table, Me is methyl, Boc is t-butoxycarbonyl, i-Bu is isobutyl and Ac is acetyl.
[Process for Preparation of the Compounds of the Present Invention]
(a) The compounds of the formula (I), wherein E is xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94NR9COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94COxe2x80x94, i.e., the compounds of the present invention of the formula (I-A) 
(wherein, R1-1 is the same meaning as hereinbefore described for R1, provided that amino group in 1-1 is protected with protecting group, if necessary, R3-1 is the same meaning as hereinbefore described for R3, provided that amino group in R3-1 is protected with protecting group, if necessary, R4-4 is the same meaning as hereinbefore described for R4, provided that xe2x80x94COOH, hydroxy or amino group in R4-4 is protected with protecting group, if necessary, J3 is the same meaning as hereinbefore described for J, provided that amino or hydroxy group in J3 is protected with protecting group, if necessary, E1 is xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR8xe2x80x94, xe2x80x94NR9COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94COxe2x80x94 and the other symbols are the same meanings as defined hereinbefore) may be prepared by amidation or esterification of the compounds of the formula (II) 
(wherein all the symbols are the same meanings as defined hereinbefore) with the compounds of the formula (III)
J4xe2x80x94R4-4xe2x80x83xe2x80x83(III)
(wherein, J4 is xe2x80x94OH, xe2x80x94NHR16, xe2x80x94NHR17, xe2x80x94NR21xe2x80x94NHR20, xe2x80x94NR23xe2x80x94(C1-4 alkylene)-NHR22, xe2x80x94Oxe2x80x94(C1-4 alkylene)-NHR24, xe2x80x94Sxe2x80x94(C1-4 alkylene)-NHR25 or heterocyclic ring possessing NH (this heterocyclic ring is the same meaning as hereinbefore described for the heterocyclic ring represented by each R4-2 and R16, L and R16, R4-1 and R17, R4-2 and R17, and L and R17 taken together with nitrogen atom to which they are attached) (in which all the symbols are the same meanings as defined hereinbefore), R4-4 is the same meaning as defined hereinbefore), or by amidation or esterification of the compounds of the formula (IV) 
(wherein, E2 is xe2x80x94COOH, xe2x80x94NHR9 (in which R9 is the same meaning as defined hereinbefore) or xe2x80x94OH and the other symbols are the same meanings as defined hereinbefore) with the compounds of the formula (V)
E3xe2x80x94R3-1xe2x80x83xe2x80x83(V)
(wherein, E3 is xe2x80x94OH, xe2x80x94NHR8 (in which R8 is the same meaning as defined hereinbefore) or xe2x80x94COOH and the other symbols are the same meanings as defined hereinbefore).
The amidation is well known. For example, it may be carried out
(1) by the method with using acid halide,
(2) by the method with using mixed acid anhydride,
(3) by the method with using conducing agent etc.
Concrete description of these methods are as follows:
(1) Method with using acid halide may be carried out, for example; carboxylic acid is reacted with an acid halide (oxalyl chloride, thionyl chloride or isobutyl chloroformate etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran or ethyl acetate etc.) or without solvents at from xe2x88x9220xc2x0 C. to a refluxing temperature to give an acid halide. The obtained acid halide and an amine are reacted in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or N-methylmorpholine etc.) at 0xcx9c40xc2x0 C.
(2) Method with using mixed acid anhydride may be carried out, for example; carboxylic acid is reacted with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, ethyl chloroformate, isobutyl chloroformate etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran. etc.) or without solvents, in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or N-methylmorpholine etc.) at xe2x88x9220xcx9c40xc2x0 C. to give mixed acid anhydride. The obtained mixed acid anhydride and corresponding amine are reacted in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) at 0xcx9c40xc2x0 C.
(3) Method with using condensing agent may be carried out, for example; a carboxylic acid and an amine are reacted in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran. etc.) or without solvents in the presence or absence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) using with condensing agent (1,3-dicyclohexylcarbodiimido (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC), 2-chloro-1-methylpyridinium iodide, 1,1xe2x80x2-carbonydiimidazole (CDI) etc.) using or without 1-hydroxybenztriazole (HoBt) at 0xcx9c40xc2x0 C.
Preferably, the above reactions (1), (2) and (3) described above are carried out under an atmosphere of an inert gas (argon, nitrogen etc.) on anhydrous condition.
The esterification may be carried out by the same procedure as described in the above amidation.
The compounds of the formula (I-A), wherein E1 is xe2x80x94Sxe2x80x94 i.e., the compounds of the formula (I-A-1) 
(wherein all the symbols are the same meanings as defined hereinbefore) may be prepared by reacting the compounds of the formula (VI) 
(wherein all the symbols are the same meanings as defined hereinbefore) with the compounds of the formula (VII)
Xxe2x80x94R3-1xe2x80x83xe2x80x83(VII)
(wherein, X is halogen and the other symbols are the same meanings as defined hereinbefore).
The reaction of the compounds of the formula (VI) and the compounds of the formula (VII) may be carried out by known methods. For example, it may be carried out in an organic solvent (dimethylformamide, aceton etc.) in the presence of base (potassium carbonate etc.) at 0xcx9c40xc2x0 C.
(b) The compounds of the formula (I), wherein E is xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, i.e., the compounds of the formula (I-B) 
(wherein, E4 is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94 and the other symbols are the same meanings as defined hereinbefore) may be prepared by oxidadtion of the said compounds of the formula (I-A) wherein E1 is xe2x80x94Sxe2x80x94.
The oxidation is known per su. In case of oxidation of sulfide into sulfoxide, it may be carried out, for example, in an organic solvent (methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.) in the presence of one equivalent of oxidizing agent (hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, peracid (e.g., m-chloroperbenzoic acid, peracetic acid etc.) etc.) for a few minutes at xe2x88x9278xcx9c0xc2x0 C.
In case of oxidation of sulfide into sulfon, it may be carried out, for example, in an organic solvent (methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.) in the presence of an excessive amount of oxidizing agent (hydrogen peroxide, sodium periodate, potassium permanganate, sodium perbromate, potassium peroxymonosulfate, peracid (e.g., m-chloroperbenzoic acid, peracetic acid etc.) etc.) for a few hours at xe2x88x9278xcx9c40xc2x0 C.
(c) The compounds of the formula (I), wherein E is xe2x80x94NR10xe2x80x94, i.e., the compounds of the formula (I-C) 
(wherein all the symbols are the same meanings as defined hereinbefore) may be prepared by reacting the compounds of the formula (VIII) 
(wherein all the symbols are the same meanings as defined hereinbefore) with the compounds of the formula (IX)
NHR10xe2x80x94R3-1xe2x80x83xe2x80x83(IX)
(wherein all the symbols are the same meanings as defined hereinbefore).
The reaction of the compounds of the formula (VIII) and the compounds of the formula (IX) may be carried out by known methods, for example, by reacting the compounds of the formula (VIII) and the compounds of the formula (IX) in an organic solvent (methanol, ethanol etc.) using reductant (sodium cyanoborohydride, sodium borohydride, etc.) or, using pH adjustifying agent (acetic acid etc.) if necessary, at 0xcx9c40xc2x0 C.
(d) The compounds of the formula (I), wherein E is xe2x80x94SO2NR11xe2x80x94, i.e., the compounds of the formula (I-D) 
(wherein all the symbols are the same meanings as defined hereinbefore) may be prepared by reacting the compounds of the formula (X) 
(wherein all the symbols are the same meanings as defined hereinbefore) with the compounds of the formula (XI)
NHR11xe2x80x94R3-1xe2x80x83xe2x80x83(XI)
(wherein all the symbols are the same meanings as defined hereinbefore).
The reaction of the compounds of the formula (X) and the compounds of the formula (XI) may be carried out by known methods, for example, by reacting the compounds of the formula (X) with base (triphenylphosphine etc.) and acid halide (oxazolyl chloride, thionyl chloride etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofran etc.), at from xe2x88x9220xc2x0 C. to refluxing temperature, and then by reacting thus obtained compounds and the compounds of the formula (XI) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofran etc.) at 0xcx9c40xc2x0 C.
(e) The compounds of the formula (I), wherein E is xe2x80x94NR12SO2xe2x80x94, i.e., the compounds of the formula (I-E) 
(wherein all the symbols are the same meanings as defined hereinbefore) may be prepared by reacting the compounds of the formula (XII) 
(wherein all the symbols are the same meanings as defined hereinbefore) with the compounds of the formula (XIII)
Xxe2x80x94SO2xe2x80x94R3-1xe2x80x83xe2x80x83(XIII)
(wherein, X is halogen and the other symbols are the same meanings as defined hereinbefore).
The reaction of the compounds of the formula (XII) and the compounds of the formula (XIII) may be carried out, for example, by reacting the compounds of the formula (XII) and the compounds of the formula (XIII) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) at 0xcx9c40xc2x0 C.
(f) The compounds of the formula (I), wherein A is xe2x80x94COxe2x80x94 or xe2x80x94SO2xe2x80x94, i.e., the compounds of the formula (I-F) 
(wherein, A1 is xe2x80x94COxe2x80x94 or xe2x80x94SO2xe2x80x94 and the other symbols are the same meanings as defined hereinbefore) may be prepared by amidation or sulfonamidation of the compounds of the formula (XIV) 
xe2x80x83(wherein all the symbols are the same meanings as defined hereinbefore) with the compounds of the formula XV)
R1-1xe2x80x94A2xe2x80x83xe2x80x83(XV)
(wherein, A2 is xe2x80x94COOH or xe2x80x94SO3H and the other symbols are the same meanings as defined hereinbefore).
The amidation and sulfonamidation may be carried out by the same procedure as described hereinbefore.
(g) The compounds of the formula (I), wherein A is single bond and R1 is C1-4 alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring, i.e., the compounds of the formula (I-G) 
(R1-2 is C1-4 alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring (with the proviso that when amino group exists as a substituent of each ring, such an amino group is protected with protecting group, if necessary) and the other symbols are the same meanings as defined hereinbefore) may be prepared by reacting the compounds of the formula (XIV) 
(wherein all the symbols are the same meanings as defined hereinbefore) with the compounds of the formula (XVI)
R1-3xe2x80x94CHOxe2x80x83xe2x80x83(XVI)
(wherein, R1-3 is phenyl, C3-8 cycloalkyl, heterocyclic ring or C1-3 alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring (with the proviso that when amino group exists as a substituent of each ring, such an amino group is protected with protecting group, if necessary)).
This reaction may be carried out by the same procedure as described in the reaction of the compounds of the formula (VIII) and the compounds of the formula (IX).
(h) The compounds of the formula (I), wherein R1 is heterocyclic ring containing at least one nitrogen atom or C1-4 alkyl substituted with heterocyclic ring containing at least one nitrogen atom and the said heterocyclic ring is substituted with C2-5 acyl or C1-4 alkoxycarbonyl, i.e., the compounds of the formula (I-H) 
(wherein, R43 is single bond or C1-4 alkylene, R44 is C1-4 alkoxycarbonyl or C2-5 acyl, R45 is C1-4 alkyl, C1-4 alkoxy, phenyl, phenoxy, benzyloxy, xe2x80x94SR5, halogen, nitro or xe2x80x94NR6R7, n is 0-2 and 
is the same meaning for heterocyclic ring in R1, provided that such a heterocyclic ring contains at least one nitrogen atom and that when amino group exists as a substituent represented by R45, such an amino group is protected with protecting group, if necessary and the other symbols are the same meanings as defined hereinbefore) may be prepared by amidation of the compounds of the formula (XVII) 
(wherein all the symbols are the same meanings as defined hereinbefore) with the compounds of the formula (XVIII)
R44xe2x80x94OHxe2x80x83xe2x80x83(XVIII)
(wherein, R44 is the same meaning as defined hereinbefore).
The amidation may be carried out by the same procedure as described hereinbefore.
(i) Among the compounds of the formula (I), the compounds of the formula (I-I) 
(wherein, R1-4, R3-2, R4-5 and J4 are the same meanings as hereinbefore described for R1, R3, R4 and J respectively, provided that at least one of them is a group containing xe2x80x94COOH, hydroxy or amino and the other symbols are the same meanings as defined hereinbefore) may be prepared by removal of protecting group according to alkaline hydrolysis, by removal of protecting group in an acidic condition and/or by hydrogenolysis of the compounds of the said formulae (I-A), (I-A-1), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G) or (I-H).
The removal of a protecting group according to alkaline hydrolysis is well known. For example, it may be carried out in an organic solvent (methanol tetrahydrofuran, dioxane etc.), using hydroxide of an alkaline metal (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.), hydroxide of an alkaline earth metal (calcium hydroxide etc.) or carbonate (sodium carbonate, potassium carbonate etc.) or an aqueous solution thereof or a mixture thereof at 0xcx9c40xc2x0 C.
The removal of a protecting group in an acidic condition is well known. For example, it may be carried out in an organic solvent (methyhlene chloride, chloroform, dioxane, ethyl acetate, anisole etc.) or without solvent, in the presence of organic acid (trifluoroacetic acid, methanesulfonic acid, trimethylsilyliodide etc.) or inorganic acid (hydrochloric acid etc.) or a mixture thereof (bromohydroacetic acid etc.) at 0xcx9c90xc2x0 C.
The hydrogenolysis is well known. For example, it may be carried out in an organic solvent (tetrahydrofran, dioxane, diethyl ether, ethyl acetate, methanol, ethanol etc.), in the presence of catalyst to hydrogenate (e.g., Pdxe2x80x94C, palladium, palladium hydroxide, palladium acetate, palladium black, platinum black, Ni, Raney nickel etc.), at an ordinary or increased pressure under an atmosphere of hydrogen gas at 0xcx9c80xc2x0 C.
As well known to the person in the art, a protecting group of carboxy or hydroxy includes, for example, t-butyl, benzyl etc. In addition, such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991. A protecting group of amino includes, for example, benzyloxycarbonyl, t-butoxycarbonyl. In addition, such a group includes the other protecting group which is removable selectively and easily. Further, the aimed compounds of the present invention may be prepared easily by choice of these protecting group.
The compounds of the formulae (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII) may be known per su or may be prepared by known methods or the methods described in Examples. But, the above compounds may be prepared by the other methods.
For example, the compounds of the formula (X) may be prepared by the method described in Liebigs Ann. Chem, 776-783, 1979.
For example, the compounds of the formula (XII) may be prepared by the method described in J. Org. Chem., Vol. 44, No. 10, 1979.
For example, the compounds of the formula (XIV), wherein E is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, -SO2xe2x80x94, i.e., the compounds of the formula (XIVxe2x80x2) and the compounds of the formula (XVII), wherein E is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, i.e., the compounds of the formula (XVIIxe2x80x2) may be prepared by the method shown in the following Reaction Schemes 1 and 2.
Further, among the compounds of the formula (II), the compounds of the formula (IIxe2x80x2) 
(wherein all the symbols are the same meanings as defined hereinbefore) may be prepared by the method shown in the following Reaction Scheme 3. 
(In each Reaction Scheme, E5 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or SO2xe2x80x94, Boc is t-butoxycarbonyl, (Boc) 2O is di-t-butyl dicarbonate, R46 is single bond or C1-3 alkylene, R47 is hydroxy or 2,5-dioxopyrrolidin-1-yloxy and the other symbols are the same meanings as defined hereinbefore)
The reactions described in the above-mentioned Schemes may be carried out by known methods. In the above-mentioned Schemes, compounds used for starting materials are may be known per se or may be easily prepared by known methods.
In the present invention, the other starting materials and each reagent are known per se or may be prepared by known methods.
In each reaction in the present specification, products may be purified by a conventional manner. For example, it may be carried out by distillation at atmospheric or reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, washing or recrystallization. Purification may be carried out after each reaction or after a series of reactions.
[Pharmacological Activity]
It has been confirmed that the compounds of the present invention of the formula (I) possess an inhibitory action on N-type calcium channel according to the following experiment.
Determination of Inhibitory Activity on N-type Calcium Channel
Cell line was differentiated according to the method described in FEBS Letters, 235, 178-182, 1988. The cell was loaded with fluorescent reagent, Fura-2.AM (at the final concentration of 10 xcexcM), at 37xc2x0 C. for 30 minutes and suspended in Krebs-buffer containing HEPES (25 mM) to obtain the cell suspension. The obtained cell suspension was incubated in the presence or absence of the compounds of the present invention with nifedipine for 5 minutes. The cell was depolarized by adding potassium chloride solution (at the final concentration of 80 mM) thereto and then a fluorescence intensity at the emission wavelength of 500 nm excited by the UV of 340 nm and 380 nm alternately was measured using the intracellular calcium analyzer (Nippon Bunko Co., CAF-110). The inhibitory activity of the compound of the present invention (at the final concentration of 3 xcexcM) on calcium influx into the cell was calculated from the difference in changing the fluorescence intensity at peak (xcex94R) according to the following equation.        Inhibitory  effect  (%)  of
   the  compound  of  the
present  invention  (3  µM)
        on  calcium  flow    =            (              1        -                               Mean  of  Δ            R              in  case  of
   a  solution  containing
   the  compound  of  the 
       present  invention                                 Mean  of  Δ            R              in  case  of
a  solution  not  containing
   the  compound  of  the
        present invention                              )        xc3x97    100  
The results were shown in Table 41.
From the results of an experiment using the patch-clamp technique described in Pflxc3xcngers Archives, 391, 85-100, 1981, the compounds of the present invention at the concentration of 10 xcexcM showed clearly an inhibitory action on flux of barium ion (calcium current) passed through an N-type calcium channel. The cells used in this experiment had been incubated according to the method described in FEBS Letters, 23, 178-182, 1988.
[Toxicity]
The toxicity of the compounds of the present invention are very low and therefore, it may be considered that the compounds of the present invention are safe for pharmaceutical use.
The compounds of the formula (I) possess an inhibitory action on N-type calcium channel, so they are useful as agent for the prevention and/or treatment of cerebral infarct, transient ischemic attack, encephalomyelopathy after cardiac operation, spinal angiopathy, hypertension with stress, neurosis, epilepsy, asthma and pollakiuria etc. or agent for the treatment of pain.
For the purpose above described, the compounds of the present invention of the formula (I), non-toxic salts and acid addition salts thereof and hydrates thereof may be normally administered systematically or locally, usually by oral or parenteral administration.
The doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In the human adult, the doses per person per dose are generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 0.1 mg and 100 mg, by parenteral administration (preferred into vein) up to several times per day, or continuous administration between 1 and 24 hrs. per day into vein.
As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
The compounds of the present invention may be administered as inner solid compositions or inner liquid compositions for oral administration, or as injections, liniments or suppositories etc. for parenteral administration.
Inner solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders and granules etc. Capsules contain hard capsules and soft capsules.
In such inner solid compositions, one or more of the active compound(s) is or are, admixed with at least one inert diluent (lactose, mannitol, glucose, microcrystalline cellulose, starch etc.), connecting agents (hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate etc.), disintegrating agents (cellulose calcium glycolate etc.), lubricating agents (magnesium stearate etc.), stabilizing agents, assisting agents for dissolving (glutamic acid, asparaginic acid etc.) etc. to prepare pharmaceuticals by known methods. The pharmaceuticals may, if desired, be coated with material such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl cellulose phthalate etc., or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
Inner liquid compositions for oral administ ration include pharmaceutically-acceptable water-agents, suspensions, emulsions, syrups and elixirs etc. In such liquid compositions, one or more of the active compound(s) is or are comprised in inert diluent(s) commonly used in the art (purified water, ethanol or mixture thereof etc.). Besides inert diluents, such compositions may also comprise adjuvants such as wetting agents, suspending agents, emulsifying agents, sweetening agents, flavouring agents, perfuming agents, preserving agents and buffer agents etc.
Injections for parenteral administration include solutions, suspensions and emulsions and solid injections which are dissolved or suspended in solvent when it is used. One or more active compound(s) is or are dissolved, suspended or emulsified in a solvent when such compositions are used. Aqueous solutions or suspensions include distilled water for injection and physiological salt solution plant oil, propylene glycol, polyethylene glycol and alcohol such as ethanol etc., and mixture thereof. Such compositions may comprise additional diluents such as stabilizing agent, assisting agents for dissolving (glutamic acid, asparaginic acid, POLYSOLBATE80 (registered trade mark) etc.), suspending agents, emulsifying agents, dispersing agents, buffer agents, preserving agents etc. They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions and which can be dissolved in sterile water or some other sterile diluent for injection immediately before use.
Other compositions for parenteral administration include liquids for external use, ointments, endermic liniments, aerosols, spray compositions, suppositories and pessaries for vaginal administration etc. which comprise one or more of the active compound(s) and may be prepared by known methods.
Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents such as sodium hydrogen sulfate, stabilizing agents to give isotonicity, isotonic buffer such as sodium chloride, sodium citrate, citric acid. For preparation of such spray compositions, for example, the method described in the U.S. Pat. No. 2,868,691 or U.S. Pat. No. 3,095,355 may be used.